The disclosed subject matter relates to systems and methods for targeted drug delivery.
The exchange of molecules across the cerebral microvasculature is regulated by a unique interface known as the blood-brain barrier (BBB). Its primary function is to regulate the brain's environment in order to prevent toxins from entering the parenchyma and maintain molecular environments necessary for proper neuronal firing. The result is the effective exclusion of nearly all systemically administered compounds larger than 400 Da (Daltons) from the brain's extracellular space, rendering many neurologically potent compounds ineffective. So, potential therapeutic agents, such as inhibitors (˜1 kDa) and antibodies (30 to 300 kDa), will not reach their intended targets if administered systemically.
Focused ultrasound (FUS) in the presence of systemically administered microbubbles can locally, transiently and reversibly increase the permeability of the BBB, thus allowing targeted delivery of therapeutic agents in the brain for treatment of central nervous system diseases. Exemplary techniques for opening the BBB with FUS are described in U.S. Patent Publication Nos. 2009/0005711, 2011/0295105, 20013/0046229, each of which is incorporated by reference herein in its entirety.
Alternatively, intranasal (IN) drug administration has emerged as a promising approach for drug delivery to the brain. However, when drugs are delivered intranasally, only a small fraction of the drug can reach the CNS from the nasal cavity, which can restrict the application to very potent substances. Furthermore, drugs that are delivered intranasally can be delivered to the whole brain through this route, while neurological diseases do not generally affect the brain in a global manner. Other techniques assume that the microbubbles cross the blood-brain barrier to deliver the drug to the CNS or that the microbubble is injected intranasally.